`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208411Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`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 #
`Product Name:
`
`PMR/PMC Description:
`
`208411
`NARCAN (naloxone hydrochloride) nasal spray
`PMR #2990-1
`
`Establish reliability requirements for the combination product Narcan Nasal
`Spray (naloxone hydrochloride), and complete testing which verifies the
`combination product reliability.
`
`
`
`
`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
`
` 02/2016
` 09/2016
` 11/2016
` MM/DD/YYYY
`
`
`
`Clinical studies and batch analysis performed with the device, although conducted in limited numbers,
`demonstrated favorable rates of successful delivery.
`
`
`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 11/18/2015
`
`Page 1 of 4
`
`Reference ID: 3848740
`
`

`

`The sponsor has not demonstrated the reliability of the combination product in delivering the therapy (i.e.
`high population sample activation studies). The sponsor has not demonstrated the ability of the device to
`activate reliably after exposure to relevant preconditions, including effects of storage, transportation, and
`environmental conditions.
`
`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.
`The study will be a bench-top engineering study. It will examine the reliability of the combination
`product after simulated exposure to storage, shipping, and in-use conditions.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 11/18/2015
`
`Page 2 of 4
`
`Reference ID: 3848740
`
`

`

`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)
`Device reliability testing studies
`
`
`
`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?
`
`
`
`
`
`
`
`
`
` 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 11/18/2015
`
`Page 3 of 4
`
`Reference ID: 3848740
`
`

`

`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 11/18/2015
`
`Page 4 of 4
`
`Reference ID: 3848740
`
`

`

`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 #
`Product Name:
`
`PMR/PMC Description:
`
`
`208411
`NARCAN (naloxone hydrochloride) nasal spray
`PMR #2990-2
`
`
`Establish procedures for monitoring reports of failure of the combination
`product Narcan Nasal Spray (naloxone hydrochloride) to activate or failure
`of the combination product to deliver the full-labeled dose. Provide interim
`and final reports to the NDA, which contain a detailed analysis of reported
`device failures (including reported malfunctions that did, as well as did not
`result in patient harm), full event narratives of the failure and any
`subsequent adverse events, and the results of root cause analysis performed
`for the reported failure.
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Interim Report:
`Final Report Submission:
`
` 02/2016
` N/A
` 01/2017
`01/2018
`
`
`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
`
`
`
`Clinical studies and batch analysis performed with the device, although conducted in limited numbers,
`demonstrated favorable rates of successful delivery.
`
`
`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 11/18/2015
`
`Page 1 of 4
`
`Reference ID: 3848740
`
`

`

`The sponsor has not demonstrated the reliability of the combination product in delivering the therapy (i.e.
`high population sample activation studies). The sponsor has not demonstrated the ability of the device to
`activate reliably after exposure to relevant preconditions, including effects of storage, transportation, and
`environmental conditions.
`
`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.
`This is a requirement to monitor and report any instances of failure of the combination product to
`activate or failure of the combination product to deliver the full labeled dose.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 11/18/2015
`
`Page 2 of 4
`
`Reference ID: 3848740
`
`

`

`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)
`Device reliability reporting
`
`
`
`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?
`
`
`
`
`
`
`
`
`
` 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 11/18/2015
`
`Page 3 of 4
`
`Reference ID: 3848740
`
`

`

`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 11/18/2015
`
`Page 4 of 4
`
`Reference ID: 3848740
`
`

`

`
`
`NDA #
`Product Name:
`
`PMC #2990-3
`Description:
`
`PMR/PMC Development Template: Product Quality (CMC)
`
`NDA 208411
`NARCAN nasal spray
`PMC #2990-3
`
`
`Conduct an adequate leachable safety assessment for the
`plunger used in your container closure system. This assessment must
`include leachable data from long-term stability studies testing at least three
`batches (taking into consideration the proposed shelf-life) to determine if the
`identified extractables leach into the drug product over time. Using this
`information, conduct a toxicological risk assessment justifying the safety of
`the leachables, taking into consideration the maximum daily dose of the
`identified materials for this drug product. Submit a toxicological risk
`assessment for any leachable that exceeds 5 mcg/day. From a genetic
`toxicology perspective, any leachable that contains a structural alert for
`mutagenicity must not exceed 120 mcg/day for an acute indication, or be
`adequately qualified for safety. The risk assessment should be based on the
`maximum level of each leachable detected in long-term stability samples.
`
`Final Protocol Submission:
`Interim Report Submission:
`Final Report Submission:
`Other:
`
`
` 02/2016
` 01/2017
` 11/2017
` MM/DD/YYYY
`
`
`PMC Schedule Milestones:
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMC instead of a pre-approval
`requirement. Check reason below and describe.
` Need for drug (unmet need/life-threatening condition)
` Long-term data needed (e.g., stability data)
` Only feasible to conduct post-approval
` Improvements to methods
` Theoretical concern
` Manufacturing process analysis
` Other
`
`
`
`Potential leachables from the container closure system have not been quantified to date and
`prior clinical experience does not fully address their safety. There is a concern that due to
`the nature of the materials in the container closure, some of the impurities may result in the
`potential for adverse effects. However, the rubber stopper in the container closure system
`has been used in other FDA-approved drug products. Given the clinical experience with
`this
`plunger, and based on preliminary extractables data suggesting no significant
`concerns, this study was deemed acceptable as a post-marketing commitment.
`2. Describe the particular review issue and the goal of the study.
`
`PMR/PMC Development Template
`
`Last Updated 11/18/2015
`
`Page 1 of 2
`
`Reference ID: 3848740
`
`(b) (4)
`
`(b) (4)
`
`

`

`Although the rubber stopper that is part of the container closure system has been used in several
`FDA-approved drug products, the leachable profile of the NARCAN nasal spray has not been fully
`characterized. It is possible that chemicals from the plunger can leach into the drug solution over
`time. This study will be completed to characterize the potential leachables over stability and assess
`the safety of the container closure based on current practices.
`
`3. What type of study is agreed upon (describe and check type below)?
`Select only one. Fill out a new sheet for each type of PMR/PMC study.
` Dissolution testing
` Assay
` Sterility
` Potency
` Product delivery
` Drug substance characterization
` Intermediates characterization
` Impurity characterization
` Reformulation
` Manufacturing process issues
` Other
`
`
`Describe the agreed-upon study:
`The study is a leachable study over the course of stability to more fully characterize the
`container closure system.
`
`
`4. To be completed by ONDQA/OBP Manager:
` Does the study meet criteria for PMCs?
` Are the objectives clear from the description of the PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the 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 only)
`
`PMR/PMC Development Template
`
`Last Updated 11/18/2015
`
`Page 2 of 2
`
`Reference ID: 3848740
`
`

`

`
`
`NDA #
`Product Name:
`
`PMC #2990-4
`Description:
`
`PMC Development Template: Product Quality (CMC)
`
`NDA 208411
`NARCAN nasal spray
`PMC #2990-4
`
`Conduct a long- term stability evaluation placing at least three (3)
`manufactured lots of NARCAN Nasal Spray, 40 mg/mL, on long- term
`stability evaluation at the following temperatures:
`
`a.
`b.
`
`2 to 8°C
`40°C/75% RH - to extend the time points out to 24 months
`
`Final Protocol Submission:
`Interim Report Submission (12 months):
`Final Report Submission (24 months):
`
`
`
` 02/2016
` 06/2017
` 06/2018
`
`
`
`
`PMC Schedule Milestones:
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMC instead of a pre-approval
`requirement. Check reason below and describe.
` Need for drug (unmet need/life-threatening condition)
` Long-term data needed (e.g., stability data)
` Only feasible to conduct post-approval
` Improvements to methods
` Theoretical concern
` Manufacturing process analysis
` Other
`
`
`
`Since this product will be stored in Police cars and ambulances through the country, the stability of
`the product at temperatures ranging from 4C to 40C is needed. Some limited data is provided in the
`NDA but given the importance of the product for life-threatening conditions, a more thorough study
`is deferred to post-approval.
`
`2. Describe the particular review issue and the goal of the study.
`
`The Stability study will provide data to demonstrate that the product will remain stable, without
`precipitation or degradation, under a wide temperature range.
`
`3. What type of study is agreed upon (describe and check type below)?
`
`PMR/PMC Development Template
`
`
`Reference ID: 3848740
`
`Last Updated 11/18/2015
`
`Page 1 of 2
`
`

`

`Select only one. Fill out a new sheet for each type of PMR/PMC study.
` Dissolution testing
` Assay
` Sterility
` Potency
` Product delivery
` Drug substance characterization
` Intermediates characterization
` Impurity characterization
` Reformulation
` Manufacturing process issues
` Other
`
`
`Describe the agreed-upon study:
`The Sponsor has agreed to provide data from a 24 month study, to determine potency, dose delivery
`and potential degradation of the product when stored under vigorous conditions of low and high
`temperatures.
`
`
`
`
`
` Does the study meet criteria for PMCs?
` Are the objectives clear from the description of the PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the 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 only)
`
`PMR/PMC Development Template
`
`
`Reference ID: 3848740
`
`Last Updated 11/18/2015
`
`Page 2 of 2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANA L WALKER
`11/18/2015
`
`JUDITH A RACOOSIN
`11/18/2015
`
`Reference ID: 3848740
`
`

`

`505(b)(2) ASSESSMENT
`
`NDA # 208411
`
`Application Information
`NDA Supplement #: S-
`Efficacy Supplement Type SE-
`
`Proprietary Name: Narcan Nasal Spray
`Established/Proper Name: naloxone hydrochloride nasal spray
`Dosage Form: liquid, intranasal spray
`Strengths: 4 mg per unit-dose sprayer (100 mcL)
`Applicant: Adapt Pharma Operations Limited
`
`Date of Receipt: July 20, 2015
`
`PDUFA Goal Date: January 20, 2016
`
`RPM: Diana Walker
`Proposed Indication: Treatment of known or suspected opioid overdose, as manifested by
`respiratory and/or central nervous system depression.
`
`Action Goal Date (if different):
`November 18, 2015
`
`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 staff in the Immediate Office, Office of New Drugs.
`
`Reference ID: 3848914
`
`Page 1
`Version: January 2015
`
`

`

`INFORMATION PROVIDED VIA RELIANCE
`(LISTED DRUG OR LITERATURE)
`
`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)
`Narcan (naloxone hydrochloride; NDA
`016636)
`
`Information relied-upon (e.g., specific
`sections of the application or labeling)
`
`The Applicant owns this NDA and is
`cross-referencing the Agency’s previous
`findings of safety and effectiveness for
`Narcan
`
`Published Literature
`
`Pediatric assessment: Narcan is
`approved for the full pediatric age range;
`however, labeling recommends weight-
`based dosing. The proposed product is a
`fixed dose. Therefore, the Applicant was
`required to submit literature to support
`the safety and effectiveness of this fixed
`dose of naloxone for the entire pediatric
`age range.
` *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 applicant bridged to the findings for Narcan (NDA 016636), which the Applicant owns,
`by conducting a relative bioavailability study (study Naloxone-Ph1a-002) comparing the
`proposed final to-be-marketed product to an ANDA product of Narcan (NDA 016636)
`because Narcan was discontinued for marketing purposes. The ANDA product (Naloxone
`hydrochloride for IM injection) that was used in the relative bioavailability study was
`sourced from a commercial supplier and manufactured by Hospira Inc., Lake Forest, IL.
`
`Literature was required as part of the pediatric assessment to support pediatric labeling.
`These studies either list Narcan or the generic name, naloxone, and the Applicant established
`a bridge to their Narcan NDA by conducting a relative bioavailability study.
`
`RELIANCE ON PUBLISHED LITERATURE
`
`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: 3848914
`
`Version: January 2015
`
`

`

`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.
`The literature is required for the pediatric assessment to support pediatric labeling
`
`(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).
`Narcan
`
`(c) Are the drug product(s) listed in (b) identified by the applicant as the listed drug(s)?
` YES
` NO
`
`The Applicant owns the Narcan NDA (NDA 16636)
`
`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
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`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.
`
`The Applicant is not relying on the Agency’s finding of safety and efficacy for Narcan (NDA
`16636), instead, they are cross-referencing this NDA, which they own, to support the
`Narcan nasal spray NDA.
`
`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)
`
`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:
`
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`c) Described in a final OTC drug monograph?
` NO
` YES
`If “YES”, please list which drug(s).
`
`Name of drug(s) described in a final OTC drug monograph:
`
`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:
`
`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 Regi