`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`022549Orig1s000
`
`
`
`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/BLA #
`
`~ 022549
`
`Product Name:
`
`
`Adasuve (loxapine) inhalation powder
`
`1 891 -1
`
`PMR/PMC Description: A deferred pediatric study under PREA for the acute treatment of
`agitation associated with schizophrenia or bipolar I disorder in pediatric
`patients ages 10 to 17 years.
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`5/1/2013
`
`7/1 8/2013
`Study/Trial Completion:
`1/18/2014
`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.
`
`[:1 Unmet need
`|:I Life-threatening condition
`El Long-term data needed
`IE Only feasible to conduct post-approval
`[:1 Prior clinical experience indicates safety
`|:I Small subpopulation affected
`E] Theoretical concern
`[:1 Other
`
`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.”
`
`
`We are deferring submission of the pediatric study for ages 10 to 17 years for this
`application because this product is ready for approval for use in adults and the pediatric
`
`studies have not been completed.
`
`PMR/PMC Development Template
`
`Last Updated 12/21/2012
`
`Page 1 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`3.
`
`If the study/clinical trial is a PMR, check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`
`El Accelerated Approval (subpart H/E)
`El Animal Efficacy Rule
`[Z Pediatric Research Equity Act
`I:I FDAAA required safety study/clinical trial
`
`—
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`. I:| Assess a known serious risk related to the use of the drug?
`El Assess signals of serious risk related to the use of the drug?
`I:I 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:
`
`El 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
`
`I:I Analysis using pharmacovigilanc_e_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
`
`E] 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
`
`|:I 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
`subj ects?
`
`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 study to obtain pharmacokinetic data and provide information pertinent to dosing of
`
`ADASUVE in the relevant population (pediatric population).
`
`Required
`
`El Observational pharmacoepidemiologic study
`El Registry studies
`El Primary safety study or clinical trial
`El Pharrnacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`El Thorough Q-T clinical trial
`El Nonclinical (animal) safety study (e. g., carcinogenicity, reproductive toxicology)
`
`PMR/PMC Development Template
`
`Last Updated 12/21/2012
`
`Page 2 of 3
`
`Reference ID: 3240292
`Reference ID: '3240292
`
`

`

`Continuation 0
`
`uestion 4
`
`E] Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`IX Pharrnacokinetic studies or clinical trials
`I:I Drug interaction or bioavailability studies or clinical trials
`E] Dosing trials
`E] Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`
`|:I Meta-analysis or pooled analysis of previous studies/clinical trials
`E] Irnmunogenicity as a marker of safety
`D Other (provide explanation)
`
`
`Agreed upon:
`
`El Quality study without a safety endpoint (e.g., manufacturing, stability)
`E] Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
`'
`El 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
`El Dose-response study or clinical trial performed for effectiveness
`E] Nonclinical study, not safety-related (specify)
`
`
`D Other
`
`
`5 .
`
`Is the PMR/PMC clear, feasible, and appropriate?
`
`IE Does the study/clinical trial meet criteria for PMRs or PMCs?
`[X Are the objectives clear from the description of the PMR/PMC?
`E Has the applicant adequately justified the choice of schedule milestone dates?
`E Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`PMRfi’IMC Development Coordinator:
`
`This PMR/PMC has been reviewedfor clarity and consistency, and is necessary tofurtlzer refine
`the safety, eflicacy, 0r optimal use ofa drug, or to ensure consistency and reliability ofdrug
`quality.
`
`
`
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 12/21/2012
`
`Page 3 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`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 #
`
`022549
`
`Product Name:
`
`Adasuve (loxapine) inhalation powder
`
`1 891 —2
`
`PMR/PMC Description: A deferred pediatric study under PREA for the acute treatment of
`agitation associated with schizophrenia or bipolar I disorder in pediatric
`patients ages 10 to 17 years.
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`10/1/2013
`
`9/30/2014
`Study/Trial Completion:
`3/30/2014
`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.
`
`-
`I: Unmet need
`[:l Life-threatening condition
`E] Long—term data needed
`[Z Only feasible to conduct post-approval
`I:I Prior clinical experience indicates safety
`El Small subpopulation affected
`E] Theoretical concern
`[:1 Other
`
`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.”
`
`
`We are deferring submission of the pediatric study for ages 10 to 17 years for this
`application because this product is ready for approval for use in adults and the pediatric
`
`studies have not been completed.
`
`PMR/PMC Development Template
`
`Last Updated 12/21/2012
`
`Page 1 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`3.
`
`If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`
`— Which regulation?
`[:I Accelerated Approval (subpart H/E)
`El Animal Efficacy Rule
`[Z] Pediatric Research Equity Act
`E] FDAAA required safety study/clinical trial
`
`—
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`E] Assess a known serious risk related to the use of the drug?
`El Assess signals of serious risk related to the use of the drug?
`E] 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:
`El AnabLsis of spontaneous postmarketirlggdverse 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
`
`E] Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharrnacovigilance 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
`
`[I 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
`
`I:I 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 study of the efficacy and safety of ADASUVE in the relevant pediatric population.
`
`Required
`
`El Observational pharmacoepidemiologic study
`I:I Registry studies
`[Z Primary safety study or clinical trial
`I:I Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`|:I Thorough Q—T clinical trial
`E] Nonclinical (animal) safety study (e. g., carcinogenicity, reproductive toxicology)
`
`PMR/PMC Development Template
`
`Last Updated 12/21/2012
`
`Page 2 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`Continuation 0
`
`uestion 4
`
`El Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`El Pharmacokinetic studies or clinical trials
`El Drug interaction or bioavailability studies or clinical trials
`El Dosing trials
`E] Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`
`El Meta-analysis or pooled analysis of previous studies/clinical trials
`El Immunogenicity as a marker of safety
`[:1 Other (provide explanation)
`
`
`Agreed upon:
`
`El Quality study without a safety endpoint (e. g., manufacturing, stability)
`El Pharmacoepidemiologic study not related to safe drug use (e. g., natural history of disease,
`background rates of adverse events)
`[:1 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
`I:I Dose-response study or clinical trial performed for effectiveness
`El Nonclinical study, not safety-related (specify)
`
`'
`
`[:1 Other
`
`
`5.
`
`Is the PMR/PMC clear, feasible, and appropriate?
`
`[2 Does the study/clinical trial meet criteria for PMRs or PMCS?
`IX] Are the objectives clear from the description of the PMR/PMC?
`IX] 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/P C Development Coordinator:
`This PMR/PMC has been reviewedfor clarity and consistency, and is necessary to further refine
`the safety, eflicacy, 0r optimal use ofa drug, or to ensure consistency and reliability ofdrug
`quality.
`
`
`
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 12/21/2012
`
`Page 3 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`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:
`
`022549
`
`
`Adasuve (loxapine) inhalation powder
`
`1 891 —3
`PMR/PMC Descriptioni You are required to conduct a large, non-randomized, open—label,
`postmarketing observational study to assess the risks of bronchospasm
`and related respiratory adverse events and serious outcomes (e.g.,
`hospitalization for respiratory adverse reactions, intubation, and
`mechanical ventilation) associated with ADASUVE treatment.
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`6/1/2013
`
`6/1/2015
`Study/Trial Completion:
`12/1/2015
`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.
`
`I:| Unmet need
`I:I Life—threatening condition
`El Long—term data needed
`[2 Only feasible to conduct post-approval
`[:1 Prior clinical experience indicates safety
`I:I Small subpopulation affected
`El Theoretical concern
`[:1 Other
`
`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 12/21/201211—40/204—2
`
`Page 1 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`3.
`
`If the study/clinical trial is a PMR, check the applicable regulation.
`If not aPMR, skip to 4.
`
`— Which regulation?
`E] Accelerated Approval (subpart H/E)
`E] Animal Efficacy Rule
`E] Pediatric Research Equity Act
`IE FDAAA required safety study/clinical trial
`
`—
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`[I Assess a known serious risk related to the use of the drug?
`IE Assess signals of serious risk related to the use of the drug?
`El 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:
`E] 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
`
`E] 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
`
`IE 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
`
`El 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 large, non—randomized, open-label, postmarketing observational study to assess the risks
`of bronchospasm and related respiratoryadverse events and serious outcomes (e. g.,
`hospitalization, intubation, mechanicalventilation, or rescue medication for the
`
`
`management of respiratory reactions) associated with ADASUVE treatment.
`
`
`Required
`
`[2 Observational pharrnacoepidemiologic study
`I:] Registry studies
`I:I Primary safety study or clinical trial
`E] Pharrnacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`1:! Thorough Q—T clinical trial
`|:I Nonclinical (animal) safety study (e. g., carcinogenicity, reproductive toxicology)
`
`PMR/PMC Development Template
`
`Last Updated 12/21/20124—lA297L20-12
`
`Page 2 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`Continuation 01 Question 4
`
`El Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`El Pharinacokinetic studies or clinical trials
`El Drug interaction or bioavailability studies or clinical trials
`E] Dosing trials
`El Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`[:l Meta-analysis or pooled analysis of previous studies/clinical trials
`E] Immunogenicity as a marker of safety
`C] Other (provide explanation)
`
`
`Agreed upon:
`
`E] Quality study without a safety endpoint (e.g., manufacturing, stability)
`I:I Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
`E] 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
`E] Dose-response study or clinical trial performed for effectiveness
`El Nonclinical study, not safety—related (specify)
`
`
`El Other
`
`
`5.
`
`Is the PMR/PMC clear, feasible, and appropriate?
`[Z Does the study/clinical trial meet criteria for PMRs or PMCs?
`[X Are the objectives clear from the description of the PMR/PMC?
`[Z Has the applicant adequately justified the choice of schedule milestone dates?
`IE Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`7—"?—:r:::—rz~v:7~; — v: ~ v r:—-~~>, snmzriwz :-~- -:T‘: 'rr‘it‘ --;~.—r:-:~:-r7—: “T'.?V“‘TT:":::::”:::":1»;fi'fif?‘ —-,~Mr: ‘3', «rm »-,—~——-:—7~ r—~~>, ,—,——~
`
`v: :- -- e .7. .x-xrxT—Hiw'w’ "Mue—
`
`PMR/P C Development Coordinator:
`This PMR/PMC has been reviewedfor clarity and consistency, and is necessary to further refine
`the safety, eflicacy, or optimal use ofa drug, or to ensure consistency and reliability ofdrug
`quality.
`
`
`
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 12/21/20124—14—2-9404—2
`
`Page 3 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`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 #
`
`022549
`
`Product Name:
`
`Adasuve (loxapine) inhalation powder
`
`1 891 —4
`
`PMR/PMC Description: A single-dose GLP developmental juvenile rat tolerability and
`toxicokinetic study of loxapine by inhalation route that spans the
`corresponding ages for the pediatric clinical studies (ages 10 to 17
`years).
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`‘
`
`NA
`
`NA
`Study/Trial Completion:
`5/31/2013
`‘
`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.
`
`-
`I:I Unmet need
`I:I Life-threatening condition
`[:I Long-term data needed
`IE Only feasible to conduct post-approval
`1:] Prior clinical experience indicates safety
`El Small subpopulation affected
`|:I Theoretical concern
`[:1 Other
`
`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.”
`
`The study will evaluate the potential pharmacodynamic and pharmacokinetic differences
`among different ages in rats, and the results may apply to potential differences between
`
`adults and children.
`
`PMR/PMC Development Template
`
`Last Updated 12/21/2012
`
`Page 1 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`3.
`
`If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`
`— Which regulation?
`El Accelerated Approval (subpart H/E)
`E] Animal Efficacy Rule
`[3 Pediatric Research Equity Act
`D FDAAA required safety study/clinical trial
`
`—
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`D Assess a known serious risk related to the use of the drug?
`El Assess signals of serious risk related to the use of the drug?
`D 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:
`
`I:I 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
`
`'
`
`
`E] Analysis usingpharmacovigilance 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
`
`[:I 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
`
`[:1 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.
`
`M“)
`I A single dose inhalation tolerability and toxicokinetic study in the rat,
`lb) (4)
`that span the corresponding ages proposed for the pediatric pharmacokinetic
`and efficacy trials (10 — 17 years).
`
`
`
`Required
`
`El Observational pharmacoepidemiologic study
`[:I Registry studies
`El Primary safety study or clinical trial
`[:I Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`E] Thorough Q-T clinical trial
`[:I Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`
`PMR/PMC Development Template
`
`Last Updated 12/21/2012 ‘
`
`Page 2 of 3
`
`Reference ID: 3240292
`
`

`

`Continuation o
`
`uestion 4
`
`[:1 Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`El Pharmacokinetic studies or clinical trials
`[:I Drug interaction or bioavailability studies or clinical trials
`E] Dosing trials
`E] Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`
`‘
`
`El Meta—analysis or pooled analysis of previous studies/clinical trials
`E] Immunogenicity as a marker of safety
`E] Other'(provide explanation)
`
`
`Agreed upon:
`
`1:] Quality study Without a safety endpoint (e. g, manufacturing, stability)
`I:I Pharmacoepidemiologic study not related to safe drug use (e. g., natural history of disease,
`background rates of adverse events)
`[I 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
`El Dose-response study or clinical trial performed for effectiveness
`Nonclinical study, not safety-related (specify)
`
`A single-dose GLP developmental juvenile rat tolerability and toxicokinetic study.
`D Other
`
`5.
`
`Is the PMR/PMC clear, feasible, and appropriate?
`
`E Does the study/clinical trial meet criteria for PMRs or PMCs?
`IX Are the objectives clear from the description of the PMR/PMC?
`IE Has the applicant adequately justified the choice of schedule milestone dates?
`IE Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`P
`
`C Development Coordinator:
`This PMR/PMC has been reviewedfor clarity and consistency, and is necessary to further refine
`the safety, eflicacy, 0r optimal use ofa drug, or to ensure consistency and reliability of drug
`quality.
`
`
`
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 12/21/2012
`
`Page 3 of 3
`
`Reference ID: 3240292
`Reference ID: 3240292
`
`

`

`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:
`
`022549
`
`Adasuve (loxapine) inhalation powder
`
`PMR/PMC Description:
`
`1 891 -5
`Implement, within 6 months of approval, the appropr'
`routine extraction testin with acce tance criteria for
`
`‘
`
`to ensure
`
`
`
`that levels remain below the levels that have been qualified by the risk
`assessments in Module 4.
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`Other:
`
`NA
`
`NA
`
`4/30/20 1 3
`NA
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pro-approval requirement. Check type below and describe.
`
`I] Unmet need
`D Lifethreatening condition
`[I Long-term data needed
`I: Only feasible to conduct post-approval
`El Prior clinical experience indicates safety
`[I Small subpopulation affected
`ITheoretical concern
`[I Other
`
`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.”
`
`
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`3.
`
`If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`
`— Which regulation?
`E] Accelerated Approval (subpart H/E)
`E] Animal Efficacy Rule
`[:1 Pediatric Research Equity Act
`I: FDAAA required safety study/clinical trial
`
`—
`
`—
`
`If the PIVIR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`1:] Assess a known serious risk related to the use of the drug?
`D Assess signals of serious risk related to the use of the drug?
`El 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:
`El 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
`
`E] 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
`
`D 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
`
`[:1 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.
`
`(hm)
`
`Reguired
`
`[:1 Observational pharmacoepidemiologic study
`E] Registry studies
`I:I Primary safety study or clinical trial
`El Pharmacogenetic or pharmacogenomic study or clinical trial if required to fiirther assess safety
`I: Thorough Q-T clinical trial
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`D Nonclinical (animal) safety study (e. g., carcinogenicity, reproductive toxicology)
`[:I Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`El Pharmacokinetic studies or clinical trials
`E] Drug interaction or bioavailability studies or clinical trials
`E] Dosing trials
`El Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`I:I Meta-analysis or pooled analysis of previous studies/clinical trials
`E] Immunogenicity as a marker of safety
`C] Other (provide explanation)
`
`Agreed upon:
`
`IZI Quality study without a safety endpoint (e.g., manufacturing, stability)
`El Pharmacoepidemiologic study not related to safe drug use (e. g., natural history of disease,
`background rates of adverse events)
`'
`I:] 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
`El Dose-response study or clinical trial performed for effectiveness
`E] Nonclinical study, not safety-related (specify)
`
`IE Other
`The results of the extractables studies on the process validation drug product batches will be
`used to guide the applicant to developing routine controls for the named volatile compounds
`that can potentially be emitted during patient use.
`
`5.
`
`Is the PMR/PMC clear, feasible, and appropriate?
`
`IX] Does the study/clinical trial meet criteria for PMRs or PMCs?
`Are the objectives clear from the description of the PMR/PMC?
`IE Has the applicant adequately justified the choice of schedule milestone dates?
`[Z Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`P
`
`C Development Coordinator:
`This PMR/PMC has been reviewedfor clarity and consistency, and is necessary to further refine
`the safety, eflicacy, 0r optimal use ofa drug, or to ensure consistency and reliability ofdrug
`quality.
`
`
`
`(signature line for BLAS)
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`505(b)(2) ASSESSMENT
`
`NDA # 022549
`
`NDA Supplement #: NA
`
`Eflicacy Supplement Type: NA
`
`Proposed Indication(s): Acute Treatment of Agitation Associated with Schizophrenia or Bipolar
`
`Proprietary Name: Adasuve
`Established/Proper Name:
`loxapine inhalation powder
`Dosage Form:
`inhalation powder
`Stren hs: 10m
`
`Applicant: Alexza Pharmaceuticals
`
`Date of Receipt: 6/21/2012 (Complete Response)
`Ori 4' I al submission — 12/11/2009; 15'
`cle CR 8-4-2011: 2"“ c cle CR 5-2-2012
`
`PDUFA Goal Date: 12/21/2012
`
`Action Goal Date (if difl'erent):
`Earlde November
`
`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
`
`|:|
`
`N0|Z|
`
`If “YES “contact the (b)(2) review staflin the Immediate Oflice, Ofiice ofNew
`Drugs.
`
`Version March 2009
`
`Reference ID: 3234692
`
`page 1
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`

`

`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 or by reliance on
`published literature. (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
`referenced product)
`Loxitane (NDA 017525)
`
`Information provided (e.g.,
`pharmacokinetic data, or specific
`sections of labeling)
`NonClinical Safety Information
`
`Loxitane IM (NDA 018039)
`
`NonClinical Safety Information
`
`
`
` *each source of information should be listed on separate rows
`
`
`3) Reliance on information regarding another product (whether a previously approved product
`or from published literature) must be scientifically appropriate. An applicant needs to
`provide a scientific “bridge” to demonstrate the relationship of the referenced and
`proposed products. Describe how the applicant bridged the proposed product to the
`referenced product(s).
`
`Alexza conducted a 14 day inhalation study in rat (Study # N106043) and a 28 day
`inhalation study in dog (Study # 78670) demonstrating that systemic exposure
`was achieved following this route of administration, and that the overall toxicity profile
`was not appreciably different than that observed following oral administration. Alexza
`conducted an in vitro metabolism study demonstrating that no novel metabolites were
`generated in lung microsomes as compared to liver microsomes (Study # AZ004-DM-
`003).
`
`
`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 necessa